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TK ☆ Thailand, 2015-09-15 14:22 (3139 d 13:31 ago) Posting: # 15399 Views: 7,506 |
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Dear All, Could anyone explain more about following sentence in EMA Guideline? "At least 2 QC sample levels should fall within the range of concentrations measured in study samples" Thing is, our inspector concluded that if 2 QC sample levels e.g. MQC and HQC exceeded the maximum concentration obtained from this analytical run, this run will be rejected because only LQC was incorporated into this run while we think on the other hand that 2 QCs should cover or closely bracket all study sample concentrations not specific for each analytical run. Please help me out to get thing more clear & Thanks a millions in advance! TK Thailand Edit: Category changed. [Helmut] |
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Ohlbe ★★★ France, 2015-09-15 14:54 (3139 d 12:59 ago) @ TK Posting: # 15400 Views: 6,497 |
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Dear TK, I would interpret this sentence more globally, not run-per-run. This is confirmed by the fact that if you need to add a QC level or to adjust the concentrations of the QCs after analysing the first runs, you are not required to re-analyse them. — Regards Ohlbe |
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TK ☆ Thailand, 2015-09-17 07:01 (3137 d 20:53 ago) @ TK Posting: # 15411 Views: 6,396 |
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Dear Ohlbe, Thanks so much for your promptly reply. Further question, let's say that our calibration curve range is 2-800 ng/mL with LQC at 6 ng/mL, MQC at 400 ng/mL and HQC at 750 ng/mL. The study drug is BCS class 4 and 50 subjects were enrolled in the study. We found Cmax of each subjects are quite varied in range from ~150 ng/mL to ~600 ng/mL. One subject has Cmax ~150 ng/mL, Four subjects have Cmax ~250 ng/mL, Around 50% of subjects have Cmax around 300-400 ng/mL and the rest 50% of subjects have Cmax around 400-600 ng/mL. While we found the low Cmax subject when we have already done half of sample analysis. Do we still need to add addition QC or adjust the curve range? If yes, how can I do it? like where to place the extra QC in the same curve range to comply the Guideline (at least 2 QCs fall within the range of concentration)? or How to narrow the curve range? Sorry if this might annoy you but I really need the answer to give to our inspector and Regulatory authorities. Thanks in advance for your kindness help! Sincerely, TK Edit: Please don’t use line-breaks within sentences in your posts – makes them difficult to follow and forces users to sroll down… [Helmut] |
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Ohlbe ★★★ France, 2015-09-17 12:35 (3137 d 15:18 ago) @ TK Posting: # 15415 Views: 6,246 |
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Dear TK, ❝ Further question, let's say that our calibration curve range is 2-800 ng/mL with LQC at 6 ng/mL, MQC at 400 ng/mL and HQC at 750 ng/mL. Preliminary observation regarding your HQC: the upper limit of the acceptance range (750 + 15 %) is 862 ng/ml, which is above your ULOQ. You will certainly get some results above 800 ng/ml, but as you are not supposed to extrapolate above the ULOQ you won't know whether they pass or fail. Your HQC concentration should not be above 695 ng/ml (upper acceptance limit 799 ng/ml). Regarding your MQC you have 2 options: - add another QC level, at a lower concentration (let's say 150 to 200 ng/ml) - lower the concentration of the existing MQC sample. 30 % of the ULOQ would be 240 ng/ml. A concentration of 240 to 300 ng/ml should be fine for most subjects. Of course you could also lower the ULOQ and adjust the MQC and HQC concentrations accordingly, but then you would have higher chances to have to dilute samples. In the end you will also have some ISR data which will show how the method performs. — Regards Ohlbe |
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Ladi ☆ Thailand, 2015-09-17 15:58 (3137 d 11:55 ago) @ Ohlbe Posting: # 15421 Views: 6,299 |
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Dear Ohlbe, ❝ "the upper limit of the acceptance range (750 + 15 %) is 862 ng/ml, which is above your ULOQ. You will certainly get some results above 800 ng/ml, but as you are not supposed to extrapolate above the ULOQ you won't know whether they pass or fail. Your HQC concentration should not be above 695 ng/ml (upper acceptance limit 799 ng/ml)." So when the EMA-BMV guideline says: "the LLOQ, within three times the LLOQ (low QC), around 30-50% of the calibration curve range (medium QC), and at least at 75% of the upper calibration curve range (high QC). The mean concentration should be within 15% of the nominal values for the QC samples," what it actually means is HQC should be 75-85% of ULOQ. Right? Regards, Ladi |
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Ohlbe ★★★ France, 2015-09-17 16:48 (3137 d 11:05 ago) @ Ladi Posting: # 15422 Views: 6,357 |
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Dear Ladi, ❝ what it actually means is HQC should be 75-85% of ULOQ. Right? Practically: yes. — Regards Ohlbe |
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TK ☆ Thailand, 2015-09-21 06:57 (3133 d 20:56 ago) @ TK Posting: # 15433 Views: 6,005 |
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Dear Ohlbe, Thanks so much for such a valuable new knowledge. Greatly appreciate it! Next time when we design our calibration curve range and QC samples, we will take this into our consideration. Sincerely, TK |
Ing. Helmut Schütz